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212
Nitric Oxide and Peroxynitrite in Health and Disease
"... II. Nitric Oxide 317 A. Discovery of nitric oxide as a biological molecule 317 B. The selective reactivity of nitric oxide 319 C. Diffusion and signaling properties of nitric oxide 319 ..."
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II. Nitric Oxide 317 A. Discovery of nitric oxide as a biological molecule 317 B. The selective reactivity of nitric oxide 319 C. Diffusion and signaling properties of nitric oxide 319
Protein aggregation and protein instability govern familial ALS patient survival. PLoS Biol 6(7): e170
, 2008
"... The nature of the ‘‘toxic gain of function’ ’ that results from amyotrophic lateral sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of debate. As a result no adequate model of any neurodegenerative disease etiology exists. We demonstrate that two synergistic properties, nam ..."
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The nature of the ‘‘toxic gain of function’ ’ that results from amyotrophic lateral sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of debate. As a result no adequate model of any neurodegenerative disease etiology exists. We demonstrate that two synergistic properties, namely, increased protein aggregation propensity (increased likelihood that an unfolded protein will aggregate) and decreased protein stability (increased likelihood that a protein will unfold), are central to ALS etiology. Taken together these properties account for 69 % of the variability in mutant Cu/Zn-superoxide-dismutase-linked familial ALS patient survival times. Aggregation is a concentration-dependent process, and spinal cord motor neurons have higher concentrations of Cu/Zn-superoxide dismutase than the surrounding cells. Protein aggregation therefore is expected to contribute to the selective vulnerability of motor neurons in familial ALS.
Boredom: A Review
- Human Factors
, 1981
"... Edward Jenner, who discovered that it is possible to vaccinate against Small Pox using material from Cow Pox, is rightly the man who started the science of immunology. However, over the passage of time many of the details surrounding his astounding discovery have been lost or forgotten. Also, the en ..."
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Edward Jenner, who discovered that it is possible to vaccinate against Small Pox using material from Cow Pox, is rightly the man who started the science of immunology. However, over the passage of time many of the details surrounding his astounding discovery have been lost or forgotten. Also, the environment within which Jenner worked as a physician in the countryside, and the state of the art of medicine and society are difficult to appreciate today. It is important to recall that people were still being bled at the time, to relieve the presence of evil humors. Accordingly, this review details Jenner’s discovery and attempts to place it in historical context. Also, the vaccine that Jenner used, which decreased the prevalence of Small Pox worldwide in his own time, and later was used to eradicate Small Pox altogether, is discussed in light of recent data.
Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature
- Hum. Mol. Genet
, 2003
"... Cu/Zn superoxide dismutase (SOD1), a crucial cellular antioxidant, can in certain settings mediate toxic chemistry through its Cu cofactor. Whether this latter property explains why mutations in SOD1 cause FALS has been debated. Here, we demonstrate motor neuron disease in transgenic mice expressing ..."
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Cu/Zn superoxide dismutase (SOD1), a crucial cellular antioxidant, can in certain settings mediate toxic chemistry through its Cu cofactor. Whether this latter property explains why mutations in SOD1 cause FALS has been debated. Here, we demonstrate motor neuron disease in transgenic mice expressing a SOD1 variant that mutates the four histidine residues that coordinately bind Cu. In-depth analyses of this new mouse model, previously characterized models and FALS human tissues revealed that the accumulation of detergent-insoluble forms of SOD1 is a common feature of the disease. These insoluble species include full-length SOD1 proteins, peptide fragments, stable oligomers and ubiquitinated entities. Moreover, chaperones Hsp25 and aB-crystallin specifically co-fractionated with insoluble SOD1. In cultured cells, all 11 of the FALS variants tested produced insoluble forms of mutant SOD1. Importantly, expression of recombinant peptide fragments of wild-type SOD1 in cultured cells also produced insoluble species, suggesting that SOD1 possesses elements with an intrinsic propensity to aggregate. Thus, modifications to the protein, such as FALS mutations, fragmentation and possibly covalent modification, may simply act to augment a natural, but potentially toxic, propensity to aggregate.
Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet 2010;19:2284–2302
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ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization
- Journal of Molecular Biology
, 2003
"... All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. ..."
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All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
Neuroprotective effects of glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector a transgenic animal model of amyotrophic lateral sclerosis
- J. Neurosci
, 2002
"... Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive lethal disease that involves selective annihilation of motoneurons. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for ALS and other motor neuron diseases. Because adeno-associated v ..."
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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive lethal disease that involves selective annihilation of motoneurons. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for ALS and other motor neuron diseases. Because adeno-associated virus (AAV) has been developed as an attractive gene delivery system with proven safety, we explored the therapeutic efficacy of intramuscular delivery of the GDNF gene mediated by an AAV vector (AAV-GDNF) in the G93A mouse model of ALS. We show here that AAV-GDNF leads to substantial and long-lasting expression of transgenic GDNF in a large number of myofibers with its accumulation at the sites of neuromuscular junctions. Detection of GDNF labeled with FLAG in the anterior horn neurons, but not �-galactosidase expressed as a control, indicates that most of the transgenic GDNF observed there is retrogradely transported
Gait dynamics in mouse models of Parkinson's disease and Huntington's disease
, 2005
"... This is an Open Access article distributed under the terms of the Creative Commons Attribution License ..."
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This is an Open Access article distributed under the terms of the Creative Commons Attribution License
Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS
- J Neurosci
"... Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We show that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and pro ..."
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We show that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated Cu 2 � /Zn 2 � superoxide dismutase 1. HGF prevented induction of caspase-1 and inducible nitric oxide synthase (iNOS) in motoneurons and retained the levels of the glial-specific glutamate transporter (excitatory amino acid transporter 2/glutamate transporter 1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity.
Wild-type SOD1 overexpression accelerates disease onset of a G85R SOD1
, 2009
"... Approximately 10 % of amyotrophic lateral sclerosis (ALS) cases are familial (FALS), and 25 % of FALS cases are caused by mutations in Cu/Zn superoxide dismutase type 1 (SOD1). Mutant (MT) SOD1 is thought to be pathogenic because it misfolds and aggregates. A number of transgenic mice have been gene ..."
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Approximately 10 % of amyotrophic lateral sclerosis (ALS) cases are familial (FALS), and 25 % of FALS cases are caused by mutations in Cu/Zn superoxide dismutase type 1 (SOD1). Mutant (MT) SOD1 is thought to be pathogenic because it misfolds and aggregates. A number of transgenic mice have been generated that express different MTSOD1s as transgenes and exhibit an ALS-like disease. Although one study found that overexpression of human wild-type (WT) SOD1 did not affect disease in G85R transgenic mice, more recent reports claim that overexpression of WTSOD1 in other MTSOD1 transgenic mice hastened disease, raising a possibility that the effect of WTSOD1 overexpression in this FALS mouse model is mutant-specific. In order to clarify this issue, we studied the effect of WTSOD1 overexpression in a G85R transgenic mouse that we recently generated. We found that G85R/WTSOD1 double transgenic mice had an acceleration of dis-ease onset and shortened survival compared with G85R single transgenic mice; in addition, there was an ear-lier appearance of pathological and immunohistochemical abnormalities. The spinal cord insoluble fraction from G85R/WTSOD1 mice had evidence of G85R–WTSOD1 heterodimers and WTSOD1 homodimers (in addition to G85R homodimers) with intermolecular disulfide bond cross-linking. These studies suggest that WTSOD1 can be recruited into disease-associated aggregates by redox processes, providing an expla-nation for the accelerated disease seen in G85R mice following WTSOD1 overexpression, and suggesting the importance of incorrect disulfide-linked protein as key to MTSOD1 toxicity.
